Semaglutide vs Endoscopic Sleeve Gastroplasty for Weight Loss

Key Points Question What is the cost-effectiveness viability of semaglutide compared with endoscopic sleeve gastroplasty (ESG) over 5 years for individuals with class II obesity? Findings In this economic evaluation study using a Markov cohort model analysis, ESG was found to be a cost-effective strategy, offering greater weight loss and cost savings. The annual cost of semaglutide would need to be reduced 3-fold, from $13 618 to $3591, for it to be a cost-competitive alternative. Meaning The study suggests that while semaglutide is effective for weight loss, it is not economically viable over the long term compared with ESG, which remains a cost-saving alternative for this patient population.


Introduction
Obesity is considered a global pandemic.In the US, the prevalence of obesity was 42.4% in 2018 and is estimated to be approximately 50% by 2030. 1,2It is associated with chronic medical conditions that affect morbidity and mortality, causing a significant burden on annual US health care spending.
In 2016, the direct medical costs of obesity were estimated to be $260 billion. 3Given the high prevalence of obesity in the US, with its adverse consequences on health and health care economics, it is important to understand the cost-effectiveness of available interventions.
Lifestyle intervention and bariatric surgery represent 2 extreme ends of the spectrum of obesity treatment.2][13] It is an incisionless, per-oral, minimally invasive endoscopic procedure that applies full-thickness sutures along the greater curvature of the stomach, from the inside, to reduce gastric capacity and alter gastric motility. 14In addition, new weight-loss medications, such as glucagon-like peptide-1 receptor agonists (eg, semaglutide and liraglutide), have recently attracted increased attention.They have several proposed mechanisms of action, including a delay in gastric emptying, which results in an increased duration of satiety and decreased appetite.
In particular, semaglutide has gained popular appeal due to its noninvasiveness, ease of use as a weekly injection, and short-term effectiveness. 15However, their widespread use could strain the budget of most payers, including Medicare. 16Although glucagon-like peptide-1 receptor agonists and ESG are seeing markedly increased use, their comparative cost-effectiveness is unknown.
In the Multicenter ESG Randomized Interventional Trial (MERIT), ESG plus lifestyle adjustments achieved a 49.2% excess weight loss at 1 year compared with 3.2% in the control group. 17On the other hand, the Semaglutide Treatment Effect in People With Obesity (STEP 1) study showed that semaglutide with lifestyle changes resulted in a 14.9% total body weight reduction over 68 weeks, a significant improvement compared with the 2.4% total body weight reduction among the placebo group, with 86.4% of semaglutide recipients losing over 5% of their body weight. 15Hence, semaglutide and ESG have established effectiveness and safety profiles from randomized clinical trials (STEP 1 and MERIT). 15,17Therefore, our economic evaluation study aimed to perform a costeffectiveness analysis of semaglutide and ESG among patients with obesity from a US health care perspective.

Model Overview
The base case was a 45-year-old patient with class II obesity (body mass index [BMI] of 35-39.9 [calculated as weight in kilograms divided by height in meters squared]) and a BMI of 37.For this economic evaluation study conducted from September 1, 2022, to May 31, 2023, we developed a state-transition Markov cohort model to assess the cost-effectiveness of 2 strategies: semaglutide and ESG.The model time horizon was 5 years to capture the outcomes of interest.The first-year clinical data were derived from 2 randomized clinical trials (STEP 1 [semaglutide] and MERIT [ESG]). 15,178][19][20][21][22][23][24][25][26][27]

Competing Strategies for Management of Class II Obesity
We simulated 2 treatment strategies vs no treatment: semaglutide and ESG.Our reference group included patients who did not undergo any treatment for weight loss and had a slight weight gain over time based on published literature. 21Patients in the semaglutide group faced the risk of dropping out of the strategy due to medication intolerance. 15,19,22,23Based on published literature, patients who dropped out of the weight loss strategy regained weight. 20,29Patients in the ESG group faced the risk of severe adverse events (defined as class 3-5 on the Clavien-Dindo classification scale, 30 requiring surgical, endoscopic, or radiologic intervention) and adverse events (defined as class 1-2 on the Clavien-Dindo classification scale, including accommodative gastrointestinal symptoms), which were based on data from the MERIT trial. 17Adverse event rates for the ESG strategy were applied for the first year after the procedure.Patients who did not have a satisfactory response underwent repeat ESG.For model input, weight change was converted to the rate of BMI change. 26,29,31The background mortality table for the year 2020 in the US was adjusted for age, sex, and BMI using data from the US Third National Health and Nutrition Examination Survey. 32

Costs and Quality-of-Life Adjustments
The model costs assume a US health care system's perspective.The cost of no treatment was assumed to be zero.The model incorporated costs of ESG, repeat ESG, associated adverse events from ESG, and the monthly cost of semaglutide. 25,27All costs from prior years were adjusted to 2022 US dollars using the Consumer Price Index. 33Patients in the ESG group received an initial quality-oflife decrement associated with the procedure, which was applied for 1 week.The association of adverse events from ESG with quality of life was also incorporated; a quality-of-life decrement was applied for 2 weeks each for severe adverse events and adverse events. 24,25We did not apply any quality-of-life decrement for semaglutide intolerance or adverse events because this typically involves stopping the medication and recurrence of weight gain, which is already captured in the model.We did not apply any cost associated with obesity because the model schematic did not project resolution of obesity; however, we instead incorporated improvement in quality of life with weight loss.We applied a quality-of-life improvement of 0.0056 quality-adjusted life-years (QALYs) per BMI unit decrease, as used previously. 26,29,31Costs and utilities were discounted at an annual rate of 3%. 34

Outcomes
Our outcomes of interest were QALYs, total costs, and incremental cost-effectiveness ratios (ICERs), which were calculated as differences in costs and QALYs between the competing strategies.A willingness-to-pay threshold of $100 000 per QALY was used to evaluate cost-effectiveness.

Statistical Analysis
To ensure the robustness and reliability of our model's outcomes, we conducted a comprehensive sensitivity analysis, including 1-way, 2-way, and probabilistic sensitivity analyses.Deterministic We assumed that patients who dropped out from the semaglutide strategy experienced weight loss for at least 3 months before starting to regain weight.For the ESG strategy, a proportion of patients with insufficient weight loss or weight regain underwent repeat ESG after the first year.
Although MERIT or other published literature did not report any mortality associated with ESG, patients faced a 30-day mortality risk in our model based on expert opinion.We made this assumption based on the procedure's invasiveness compared with semaglutide.The analysis was conducted using TreeAge Pro, version 2023 R2 (TreeAge Software).

Results
In the base-case analysis, the QALYs accumulated over 5 years were 3.55 for no treatment, 3.60 for semaglutide, and 3.66 for ESG (  2).However, when the time horizon was extended to 2 years, ESG became cost saving and dominated the semaglutide strategy.
We performed sensitivity analyses over a 5-year time horizon, with ESG remaining cost saving in all analyses, with an ICER of -$595 532 per QALY for the base case (Figure 1).Probabilistic sensitivity analysis was performed on the model over varied time horizons.With the use of a willingness-to-pay threshold of $100 000 per QALY, ESG was cost-effective compared with semaglutide, with a probability of 1.00%, 80.90%, 99.97%, 100%, and 100% over 1, 2, 3, 4, and 5 years, respectively (Table 3).At a 1-year time horizon, the cost required for the ESG procedure to become cost-effective compared with semaglutide with an ICER threshold of $100 000/QALY, currently $16 360, was $11 098 (eFigure 2 in Supplement 1).The annual price of semaglutide to achieve nondominance compared with ESG with an ICER threshold of $100 000/QALY over a 5-year time horizon was $3591 and is currently at $13 618 (Figure 2).Two-way sensitivity analyses of the annual cost of semaglutide to clinically relevant parameters demonstrated that the choice of strategy  -800 000 -750 000 -700 000 -650 000 -600 000 -550 000 -500 000 -450 000 -400 000 -350 000 -300 000 would only change if the cost of semaglutide decreased by at least 3-fold (eFigure 3A-D in Supplement 1).

Discussion
Our economic evalution demonstrates that ESG achieved and sustained greater weight loss over a 5-year time horizon compared with semaglutide (BMI of 31.7 vs 33.0).Furthermore, ESG is cost saving compared with semaglutide for patients with class II obesity.These results remained robust in sensitivity analyses.The strategic choice of cost-saving yet effective treatment such as ESG compared with semaglutide for specific patient groups could help alleviate the potential budget strain expected from the use of semaglutide. 16Given the high prevalence of obesity in the US, there is a growing need for cost-effective interventions that can be made accessible to the broader population-to those without the ability to pay out of pocket or from limited use of effective interventions because of budget constraints-to address the obesity pandemic.
Although few studies have assessed the cost-effectiveness of semaglutide, 27,29,31 our study is unique in comparing it with a widely performed, minimally invasive, incisionless endoscopic procedure (ie, ESG).The data from MERIT and the STEP 1 trial provide high-level evidence for ESG and semaglutide, respectively. 15,17A strength of our analyses lies in using first-year data from these randomized clinical trials with the following years' data from published literature to assess the costeffectiveness of the 2 strategies over a 5-year time horizon.This provides a reasonable time frame for comprehensively assessing the cost-effectiveness of the 2 strategies, which has important implications for patients, health care professionals, and policymakers for medical decision-making at individual and population levels.
In all 1-way sensitivity analyses over a 5-year time horizon, ESG remained cost saving, which included varying the probability of procedural mortality, quality-of-life decrements with the The cost threshold at which semaglutide can be nondominant to endoscopic sleeve gastroplasty at the 5-year time horizon is $3591.
procedure, or associated severe adverse events and adverse events.To achieve nondominance compared with ESG, the annual price of semaglutide, currently $13 618, must be $3591.This finding was further varied on 2-way sensitivity analyses with weight loss after ESG, rate of repeat ESG, weight loss with semaglutide, and dropout rate with semaglutide.It was concluded that for all parameters, the cost of semaglutide must be decreased by at least 3-fold to cause any change in the strategy preference.The Institute for Clinical and Economic Review found that the price of semaglutide must be lowered to $7494 to be cost-effective compared with lifestyle modification. 27is finding means the higher the effectiveness of the comparative strategy, the lower the cost of semaglutide required to achieve commonly accepted benchmarks for cost-effectiveness.These findings are significant for both health care professionals and patients with obesity because they compare the risks and benefits associated with a noninvasive medication against those of an emerging minimally invasive endoscopic option.
Through mathematical modeling of published literature, our study calculated that approximately 20% of patients would drop out of the semaglutide group over 5 years due to intolerance or other causes.The dropout rate due to inability to tolerate adverse events or other reasons was 7% in the STEP 1 trial and 13.5% in the STEP 8 trial over 68 weeks. 15,35This rate does not include patients who could not achieve maximal dosage.As such, we believe our estimate of a 20% dropout rate at 5 years is conservative and that the dropout rate could be higher considering continued use of the medication to maintain weight loss with costs accruing over time. 36

Limitations and Strengths
Our study has some limitations.In our analysis, we did not explicitly model the benefit associated with improvement in comorbidities, such as hypertension, hyperlipidemia, or type 2 diabetes, from either strategy.However, we accounted for this association by incorporating BMI-specific mortality, an approach that has been previously used. 26In addition, the STEP 1 trial excluded all patients with diabetes, whereas MERIT conditionally included patients with type 2 diabetes. 15,17Therefore, we adopted an approach not to include improvement in comorbidities separately in the model.
Furthermore, our study incorporated relatively short-term data for both strategies because longterm data are still accumulating.However, we did not want to make assumptions or impute data for our model and instead relied on published literature, limiting the time horizon.Our model did not account for the microlevel follow-up costs, such as routine clinic visits, assuming that these costs would be comparable for both treatment arms.Such costs are unlikely to have a significant association with the overall cost-effectiveness results, a perspective consistent with established practices in the existing literature on health care interventions. 26,37Last, we acknowledge that as more obesity medications are approved, market trends may moderately lower the price of semaglutide.However, the specialized manufacturing of peptide-based drugs implies that significant cost reductions are unlikely.
Despite these limitations, our study has several strengths.We compared ESG with semaglutide, specifically among patients with class II obesity, because it is clinically relevant and reflective of common treatment practices. 38A recent study by Saumoy et al 39 strengthens our results.Still, our study is unique because it relies exclusively on observed outcomes with minimal assumptions, enhancing the accuracy and reliability of our cost-effectiveness estimates for these treatments.Last, we ran our model over a 5-year time horizon to not only incorporate best available evidence for both strategies but also to capture health outcomes and costs comprehensively.The longer time horizon would make ESG even more cost saving.
sensitivity analyses were performed by varying one parameter at a time within prescribed bounds and recording the change in ICERs.Probabilistic sensitivity analysis is a technique that determines the association of uncertainty in various model inputs with the estimated results, addressing the variability and probabilistic nature of the model parameters.We selected specific probability distributions for each parameter based on their statistical properties and relevance to the data type (eTable in Supplement 1).Probabilistic sensitivity analyses were performed by sampling all parameters simultaneously from probability distributions.Gamma distributions were used for costs, normal distributions for weight change, and beta distributions for all other parameters.Probabilistic sensitivity analysis was performed on the model on various time horizons.In addition, we used second-order Monte Carlo simulations to incorporate parameter uncertainty into the model, running 10 000 iterations of the model, each time drawing a different set of parameters from their respective distributions.The percentage of times each strategy was cost-effective at the willingness-to-pay threshold was recorded.

Figure 1 .
Figure 1.Results of 1-Way Sensitivity Analyses Performed Over a 5-Year Time Horizon cost, semaglutide (16 341.6-10 894.4) One-way sensitivity analysis involves adjusting the value of 1 model parameter at a time to assess the association with study outcomes.This figure includes the 10 parameters with the largest association with incremental cost-effectiveness ratio (ICER) values when modified.The numbers on either side of the bars indicate the extreme parameter values associated with the resulting ICER shown in the figure.This figure is centered around the base case with an ICER of -$595 532 per quality-adjusted life-year.ESG indicates endoscopic sleeve gastroplasty; EV, expected value.
The state-transition time or model cycle length was 1 month.eFigure 1A and B in Supplement 1 shows a simplified version of the simulated strategies in the model.The study did not require institutional review board approval because it used publicly available data to simulate hypothetical patients.The study was reported in alignment with the

Table 2 .
Base-Case Results Over Different Time Horizons Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); ESG, endoscopic sleeve gastroplasty; ICER, incremental cost-effectiveness ratio; NA, not applicable; NMB, net monetary benefit; QALY, qualityadjusted life-year.

Table 3 .
Probabilistic Sensitivity Analysis Over Varied Time Horizons a